About 90 to 95% of hypertension cases are categorized as primary hypertension which means high blood pressure with no obvious underlying medical cause. The exact cause of primary hypertension is unknown, but a number of factors including increase in cardiac output (the volume of blood being pumped out by the heart) or peripheral resistance are believed to contribute to the onset of the disease. Risk factors that are related to hypertension include psychological and environmental factors such as drinking, smoking, aging, lack of exercise, obesity, too much salt in the diet, stress and the like. Genetically, when both parents have hypertension, the offspring has an 80% chance of having hypertension; if one of the parents has hypertension, the offspring has a 25 to 50% chance of having hypertension.
The ultimate goal in the treatment of hypertension is to maintain an optimal blood pressure to minimize tissue damage caused by hypertension. Thus, adopting a preventative lifestyle is as important as taking a medication. It is a goal to keep blood pressure less than 140/90 mmHg for patients with hypertension, and less than 130/80 mmHg for hypertensive patients with diabetic or nephritis complications.
If hypertension is treated, it may reduce mortality caused by stroke and cardiovascular disorders. When patients with hypertension are properly treated, it is estimated that risks of experiencing stroke, myocardial infarction and heart failure are lowered by about 35˜40%, 20˜25% and more than 50%, respectively. Lowering systolic blood pressure by 5 mmHg reduces all-cause mortality by 7% on a population basis, while mortality for coronary heart disease and stroke can be reduced by 9% and 14%, respectively. Also, blood pressure is closely related to Alzheimer's disease and, thus, blood pressure management may reduce the risk of Alzheimer's disease.
Since avoiding risk factors for cardiovascular complications is very important to hypertensive patients as explained above, continuous blood pressure management is critical to those patients. Moreover, since it is required to take medications for a long period of time in the treatment of hypertension, a combination of drugs of different mechanisms has an advantage over individual drugs in terms of preventive and therapeutic effect. Also, a combination therapy reduces doses of individual drugs, thereby reducing side effects which may occur due to long-term administration of individual drugs.
In general, medications that are often used in the treatment of hypertension are categorized into, according to their mechanism of action, diuretics, sympatholytic agents and vasodilators; and vasodilators are further categorized in accordance with their mechanism of action, as follows: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers and calcium channel blockers.
Meanwhile, hyperlipidemia is a disorder in which an excessively high level of lipids in the blood cause a buildup of plaque on the walls of the arteries, followed by inflammation and, ultimately, cardiovascular disorders. In recent years, an abnormal amount of lipids in the blood is defined as dyslipidemia.
In the treatment of hyperlipidemia, non-drug therapies such as lifestyle changes (including physical exercise and diets) and maintaining ideal body weight, may be used in conjunction with medication. Statin-based drugs are often used, and these drugs act as an HMG-CoA reductase inhibitor which has an ability to inhibit cholesterol synthesis and thereby to cause significant reduction in plasma LDL-cholesterol levels, and also result in partial reduction in triglycerides levels.
Amlodipine is a generic name for 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate, and, in particular, amlodipine besylate is commercially available under the trade name Novasc®. Amlodipine camsylate, as disclosed in Korean Patent No. 452491, shows superior solubility and stability to amlodipine besylate, and is currently available under the trade name Amodipin®. Amlodipine blocks calcium channel, and is useful in the treatment of cardiovascular disorders such as angina, hypertension and congestive heart failure.
Losartan is a generic name for 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazol-5-methanol, as disclosed in U.S. Pat. Nos. 5,608,075, 5,138,069 and 5,153,197. Currently losartan potassium is commercially available under the trade name Cozaar®. By blocking the interaction of angiotensin II and its receptor, losartan is mainly used for treating hypertension, heart failure, ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), diabetic neuropathy and glaucoma, and also for preventing the progression of post-myocardial infarction heart failure.
A combination formulation of amlodipine and losartan that have different mechanism of action from each other has an advantage over the individual drugs in terms of preventive and therapeutic effect. In addition, such formulation reduces doses of the individual drugs, thereby decreasing side effects which may occur due to a long-term administration of the individual drugs. The combination formulation is disclosed in Korean Patent Nos. 1160151, 1232296, etc., and currently sold under the trade name Amosartan®.
Rosuvastatin is a generic name for (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhep-6-enoic acid, and currently available under the trade name Crestor®. Such statin-based drugs act as an HMG-CoA reductase inhibitor which inhibits cholesterol synthesis and reduces plasma LDL-cholesterol and triglycerides concentrations. Rosuvastatin is very effective in the treatment of hypercholesterolemia, hyperlipoproteinemia or atherosclerosis.
The co-occurrence rate of hypertension and hyperlipidemia is approximately 49%, and co-administration of Amosartan® and statin-based drugs takes up about 30% in the drug treatment of cardiovascular disorders.
In clinical research, there is a growing need for a combination formulation including amlodipine, losartan and rosuvastatin having different mechanisms for more effective treatment of cardiovascular disorders. However, it is difficult to commercialize such formulation due to complexity in designing and a possibility of deterioration in dissolution and stability due to interaction among the active ingredients.
Leading to the present invention, the present inventors have conducted intensive research to redress the problems of the conventional formulations, and found that dissolution rate and stability of the active ingredients varied depending on the structure of a bilayer tablet and the manufacturing method thereof, and thus accomplished a pharmaceutical combination formulation comprising amlodipine, losartan and rosuvastatin having improved dissolution rate and stability.